When studying individuals who are infected with HIV and HCV, we found greater cognitive dysfunction in those who were coinfected (HIV/HCV) than in individuals with either viral infection alone. There is a large population of coinfected individuals who are HCV viremic and yet maintain HIV below 50 copies/ml through effective viral suppression with antiretroviral therapy (ART). New data from our laboratory show that coinfected patients are at greater risk for cognitive impairment than either HCV or viral controlled HIV- infected subjects. Our recent findings identified a monocyte type I IFN??response in some coinfected individuals that was absent in both virally suppressed HIV and HCV monoinfected individuals. Importantly, this monocyte activation profile was characterized by the expression of 6 genes that strongly correlated with cognitive impairment in coinfected individuals. Since HIVUD (undetected; <50 copies/ml) was common to both HIV mono- and coinfected individuals, the IFN activation profile in the monocytes was likely due to HCV, suggesting that successful HCV treatment might lower activation and subsequently improve cognition. In the past, the majority of coinfected subjects were not treated with standard HCV therapy due to its low success rate and frequent debilitating side effects. However, new HCV protease inhibitors (PIs) combined with peginterferon/ ribavirin (triple therapy) are an effective treatment that more consistently achieves sustained viral response (SVR). We propose to study coinfected subjects who choose to be treated and evaluate them before and after therapy for monocyte activation and changes in neuropsychological performance. We also propose to explore a mechanistic approach for the viral-induced monocyte activation on neural cell function. We show that monocytes from coinfected subjects shed exosomes containing miRNAs (miRs) that can suppress essential transcripts associated with neural cell-related targets. Our overall hypothesis is that reducing th immune activation profile by clearing HCV with treatment in coinfected individuals will result in cognitive improvement and a decrease in M/M? immune-activating miRs. Successful completion of this work will validate our peripheral monocyte markers of immune activation in coinfection that correlate with cognitive impairment plus mechanistically show how coinfection adversely affects neural cell function through activated monocyte-derived exosomal miRs.